Based on our findings during the current period of funding, this renewal application for a Conte Center for the Neuroscience of Mental Disorders posits that understanding the neurobiology of schizophrenia requires a focus on the abnormalities in cognitive processing that are present in this disorder, on the components of the dorsolateral prefrontal cortex (DLPFC) and its extrinsic connections that are likely to mediate these processes, and on the developmental events that may make these neural systems vulnerable in schizophrenia. In particular, deciphering the cascade of pathophysiological events that produces the clinical features of schizophrenia depends upon investigations that examine 1) the normal molecular, structural and functional features of DLPFC circuitry, 2) the effects of alterations in one component of the system on other elements of the circuitry, and 3) the normal development of this circuitry and the impact of genetic factors on these developmental trajectories. Moreover, the success of such an endeavor depends upon the creative blending of clinical and basic studies, each of which is guided by and informs a common central hypothesis. Consequently, in the seven integrated programs of research proposed by Center investigators, we will test complementary aspects of the following central hypothesis: Certain critical disturbances in the regulation of cognition in schizophrenia reflect functional abnormalities both in the intrinsic circuitry of the DLPFC and in its interconnections with other cortical and subcortical regions. These functional disturbances arise during postnatal development as a consequence of alterations in the molecular signals and structural elements that determine synaptic efficacy in the affected circuits. The convergent tests of this hypothesis will be conducted in a highly interactive scientific environment that integrates the basic and clinical research activities of multiple investigators from the University of Pittsburgh, in concert with faculty at the adjacent Carnegie Mellon University and with accomplished senior scientists at Princeton and Vanderbilt Universities. Collectively, our Center represents a broad array of expertise that spans molecular, developmental, systems, cognitive and clinical neuroscience. Our extensive interactions enable us to conduct a translational research program in schizophrenia that effectively transfers information from the clinic to the laboratory and back to the clinic in a truly bidirectional fashion.